Comprehensive assessment of cognitive function in adults with moderate and severe sickle cell disease
Authors: Gerard T. Portela, Meryl A. Butters, Maria M. Brooks, Leticia Candra, Caterina Rosano, Enrico M. Novelli
Journal: American Journal of Hematology (2022)

Sickle cell disease (SCD) is a group of genetic syndromes characterized by deformation of red blood cells into sickle cells, hemolysis, and downstream vascular insults. SCD carries a high burden of neurological complications including stroke, silent cerebral infarct, and cognitive impairment (CI). Few studies have characterized the pattern of CI in adults and most have been conducted in highly selected populations. A seminal study by Vichinsky et al.1 showed that adults with homozygous SCD (HbSS disease or sickle cell anemia) had CI compared with healthy controls, predominantly in psychomotor speed. However, it is difficult to generalize findings from this study to real-world SCD populations that include patients with other genotypes or important clinical factors, such as stroke and treatment with chronic transfusions. Additional studies have found significant differences in information processing/psychomotor speed between adult SCD patients and controls but no differences in other cognitive processes.2, 3 We have also previously noted that stroke is a risk factor for slower psychomotor speed, but that CI occurs independent from stroke.4 Herein, we report findings on performance in various cognitive processes and domains in a broad cross-section of adult SCD patients with a range of comorbidities, and the effects of stroke history, chronic transfusions, and SCD variants on CI. SCD patients were recruited from the University of Pittsburgh Medical Center Adult Sickle Cell Program outpatient clinic between 2016 and 2019. All patients with HbSS and HbS/β0 thalassemia (severe genotypes) or HbSC and HbS/β+ thalassemia (moderate genotypes) 18 years or older (N = 161) were informed about the study during a routine clinic visit while in steady-state (i.e., absence of acute complications). In total, 113 agreed to participate and met the following eligibility criteria: English-speaking, absence of other medical conditions associated with brain or neurocognitive dysfunction, and absence of contraindications to MRI. Healthy controls of Black race aged 18 years and older were recruited from the community and via SCD patient referral; a total of 69 were consented and eligible using similar criteria. Controls were frequency matched to patients based on age and gender. An extensive neurocognitive test battery was administered to all participants. Ten variables were calculated from the battery, including: a total score and five domain scores from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a total recall t-score and a delayed recall t-score from the Hopkins Verbal Learning Test-Revised (HVLT-R), a scaled score from the Digit Symbol Substitution Test (DSST), and an executive function domain score as a mean of scaled scores from select subsets of the Delis–Kaplan Executive Function System (D-KEFS). See Appendix S1 for details. In total, 152 participants (86 SCD patients and 66 controls) completed cognitive testing and were included in the analysis. The overall mean age of the cohort was 36.2 years (SD = 12.1), 57% were female, and average length of education was 13.7 years (SD = 2.1). SCD patients and controls had a similar distribution of age and gender, and the SCD participants were representative of the patient population at our institution in terms of relevant demographic and clinical parameters (Table S1). Across all 10 neurocognitive scores examined, patients had lower average scores than controls (Table S2). Over 50% of the patients scored below the cognitively "normal" range (>1 SD) on the HVLT-R Total Recall Score, RBANS Immediate Memory Index Score, and Language Index Score, and over 60% scored below the cognitively "normal" range on the Visuo-construction index, Attention Index, and Total Index Scores. These percentages are consistent with previous findings.1 Unadjusted linear regression analysis was conducted for each cognitive score and a multivariable-adjusted linear regression model was created for scores for which there was a significant difference by SCD status, such that β represents the estimated difference in the cognitive outcome score between the designated groups. SCD patients had lower scores on the DSST Scaled Score and Executive Function Domain Score (both P < .001), and in domains assessed by the RBANS, patients had significantly lower scores on the Language Index (P = .014), Attention Index (P < .001), and Total Index Scores (P < .001) (Table S3, Figure S1). The DSST Scaled Score (β = −1.52), Attention Index (β = −10.23), and RBANS Total Index Score (β = −6.85) were significantly lower among patients compared with controls in the multivariable logistic regression adjusting for premorbid verbal IQ, hemoglobin level, and smoking history. These findings demonstrate the pervasiveness of impairments across heterogeneous areas of cognitive function, independent of genotype. Lower DSST Scaled Score among patients reflects worse performance in attention and information processing/psychomotor speed, while lower RBANS Total Index Score among patients indicates an average of diminished abilities across immediate memory, delayed memory, language, visuo-construction, and attention. Separate multivariable linear regression models were created to evaluate the additive impact of stroke, chronic transfusion, and genotype among patients for each cognitive score for which significant adjusted differences were found between patients and controls. See Tables S4–S6 for SCD patient characteristics by stroke history, transfusion exposure, and SCD severity, respectively. In fully adjusted models using controls as the reference group, patients with a history of stroke had significantly lower DSST Scaled Score (β = −3.61), Executive Function Domain Score (β = −1.93), Attention Index Score (β = −18.00), and Total Index Score (β = −14.27), whereas patients without a history of stroke had a significantly lower Attention Index Score (β = −8.94) and Total Index Score (β = −5.63) (Table 1). Also relative to controls, patients who were not receiving transfusions had significantly lower DSST Scaled Score (β = −1.52), Attention Index Score (β = −10.27), and Total Index Score (β = −7.09). The differences for Attention Index Score (β = −9.89) and Total Index Score (β = −4.89) were reduced between patients receiving transfusions and controls, as compared with the differences between patients not receiving transfusions and controls, but remained similar for the DSST Scaled Score (β = −1.54) (Table 1). Both moderate and severe disease genotypes had lower Attention Index Score (β = −9.93 and β = −11.12, respectively) compared with controls (Table 1). Additionally, the moderate disease group had lower Total Index Score compared with controls (β = −7.42), while the severe disease group had lower DSST Scaled Score relative to controls (β = −2.05). Though we observed no differences between patients with severe and moderate genotypes, both subgroups showed deficits in various cognitive functions relative to controls, indicating the general pathophysiology of SCD may contribute to CI. Among patients, those with a history of stroke had significantly worse DSST Scaled Score (P = .015), Executive Function Domain Score (P = .012), and Total Index Score (P = .020) than patients without a history of stroke (Table 1). There were no significant differences in cognitive scores between patients receiving and those not receiving transfusions. The current findings that SCD patients with stroke have CI compared with those without stroke extend previous observations among children5 to adults with SCD. We observed that both patients with and without stroke have worse Attention Index Score and Total Index Score compared with controls. As such, our results suggest that other factors may contribute to CI in patients without a history of stroke relative to healthy individuals. We also show that not receiving chronic transfusions was associated with poorer outcomes on DSST Scaled Score, Attention Index Score, and Total Index Score compared with controls. Chronic blood transfusions may alleviate some of these impairments. However, few patients in our study were receiving chronic transfusions, and hence this finding should be confirmed in studies with a larger sample size. If confirmed, our data suggest that transfusions are protective against CI. Similar to results from Vichinsky et al.1 among patients with homozygous SCD, we found that patients with other genotypes performed significantly worse than controls in executive function and attention, as well as in global cognition, as represented by the RBANS Total Index Score. Crawford et al.2 also found that SCD patients with severe genotypes have significantly worse information processing speed. However, the authors adjusted for information processing speed among SCD patients in further analyses, which explained the significant deficits in memory, perceptual motor speed, and executive function compared with controls. Though we do not account for information processing speed in SCD patients, we demonstrate lower performance across 10 different measures of diverse cognitive domains and processes in a population of SCD patients with both severe and moderate disease. A limitation of our study is the relatively small number of confounders we included in the analysis. Arguably, other variables could also impact cognitive function and would be worthy of inclusion in an analysis conducted on a larger sample size. For instance, maternal education impacts cognitive function in children6 and may have long lasting effects throughout adulthood. Ultimately, longitudinal studies will be important to better ascertain the role of other factors. This comprehensive assessment of cognitive function in a representative SCD patient population, including those with multiple genotypes and comorbidities, revealed that patients perform worse across several cognitive processes and domains relative to controls, even after adjusting for known risk factors. Stroke remains an important contributor to CI among SCD patients, but SCD appears to affect cognitive function in the absence of stroke. Understanding the pervasiveness of CI among SCD patients can lead to identifying targeted interventions; the findings from this study can improve clinical care for SCD patients and serve as a basis for measuring the impact of treatments such as chronic transfusions on various domains of cognitive performance. The authors confirm contribution to the article as follows: study conception and design: Enrico M. Novelli, Meryl A. Butters; data collection: Leticia Candra, Meryl A. Butters; analysis and interpretation of results: Gerard T. Portela, Maria M. Brooks, Meryl A. Butters, Caterina Rosano, Enrico M. Novelli; draft manuscript preparation: Gerard T. Portela. All authors reviewed the results and revised/approved the final version of the manuscript. We wish to thank all of the participants, family members, and staff from the UPMC Adult Sickle Cell Program. Maria M. Brooks—Cerus Corporation, DSMB Member; Enrico M. Novelli—Novartis Pharmaceuticals, Consultant. Due to ongoing longitudinal data collection for this study, supporting data are not publicly available at this time. Appendix S1 Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.